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Comment by anaisbetts | Hacker News Reader

Well I mean, at the end of Shulgin's life he had heart valve damage requiring surgery (psychs cause 5-HT2B agonism which can cause heart valvulopathy), advanced dementia, and liver cancer, all three of which are likely consequences of taking psychedelics frequently. It isn't to say that there aren't benefits to taking these drugs in moderation, but if you're looking for a "Why Not", that's definitely something to think about.

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He died at 88. Didn’t have heart trouble till 82. Didn’t have dementia till 86. And he took more (types of) drugs than any human ever. So, he was just a little bit more healthy than average, no?

Edit: Thanks for sending me down the 5-HT2b rabbit hole. This was the cause of the Phen-Fen appetite suppressant heart issues. All psychedelics do seem to affect 5-HT2b receptors. I assume this is a dose dependent effect—where a daily high dose of Phen-Fen would be much more dangerous than occasional low weight psychedelic doses. But I appreciate the grounded caution and more research is clearly needed, ideally before I’m 70+.

The average American male dies at 74.2 as of 2020:

https://www.cdc.gov/nchs/products/databriefs/db427.htm

Yeah, at that age it doesn't really matter what kills you - a life that long is something to be celebrated.

All SSRIs are 5-HT2b agonists, apparently. Do people taking antidepressants have a higher instance of heart disease?

Prozac is an antagonist (not agonist) of the 5HT2C receptor at higher doses. At lower doeses the increased serotonin from SERT inhibition will stimulate 5HT2C.

https://www.pnas.org/doi/pdf/10.1073/pnas.94.5.2036

All a matter of selectivity. Most drugs affecting the Sheraton in receptions have nanomolar or better selectivity for 5-ht2A, while 1000x less binding at 5-ht2b, which in biological terms is almost inactive at normal dosing.

Is "Sheraton in receptions" speech to text for serotonin receptors :) ?

Pretty close phonetically!

Indeed, I would not really worry about this given how most people use psychs, but since you mentioned "in your old age", I thought I'd mention some effects that might be more problematic at that age vs. the average person today

True enough, but his health declined in his late 80s. David Nichols is still going strong in his late 70s, Albert Hofmann died at 102, Ram Dass died at 88. I don't see psychedelics, and their use, as being particularly risky to physical health and longevity. Especially since many of us already consume red meat, tobacco, alcohol, etc.

> I don't see psychedelics, and their use, as being particularly risky to physical health

Maybe if you don't count frying your brain as a risk to your physical health.

Is it really fried though? If I didn't want to "fry my brain" I would opt not to participate in this clusterfuck we call modern life.

Can you please explain the neuronal mechanisms involved in this frying? If you have citations I would love to read more.

So yea you put the neurons in a hot cast iron skillet, with a nice mix of butter and onions and viola - fried neurons. You can use this to baste most white meats like chicken, pork, or fish. Just please be aware that some nervous system matter has been shown to transmit prion type diseases -> so you want to make quadruply sure you got your fried neurons from a reputable dealer who has strict health controls.

You jest but my grandfather loved brains. I think it might have been a ww2 Alaskan thing? Idk. Ate them whenever he could.

Brain is delicious, umami panna cotta.

Here's a citation for a drug Shulgin is famous for:

> MDMA provides an immediate enjoyable feeling by stimulating the release of neurotransmitters, such as dopamine and serotonin in the brain. Unfortunately, abnormal regulation of the brain neurotransmitters, as well as the increased oxidative stress causes damage to the brain neurons after the MDMA exposure.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878040/

All of those studies are either in rats or mice or are in vitro. A lot of the mice and rat studies can't be translated to humans because they have significantly different metabolisms and researchers use entirely different dosages than humans do in the wild

>MDMA has been administered to approximately 1,700 human subjects with only one serious adverse reaction.

https://maps.org/mdma/

There are currently human studies of MDMA. These would probably not be moving forward if they found "brain frying" although I appreciate your willingness to read abstracts

Overdosing on MDMA can cause serotonin syndrome, which can cause neuronal death due to excitotoxicity.

Overdose on many substances is bad and can damage neurons if it crosses the BBB. That's not saying anything special about entactogens/empathogens/psychedelics

I agree.

And thats the come down after popping a pill or two at some rave in the middle of field in Essex. Fortunately the body doesnt stop making new brain cells provided one's diet is adequate.

I was surprised to learn the US Military resurrected MDMA in the 50's and then in the 70's Prof Alex Shulgin got hold of it. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931692/

Other country's handled it differently. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435835/

But it does lend credence to the conspiracy theory that the British security services started flooding the football terraces to reduce the football hooliganism that was blighting the British isles, as "documented" by later films like Football Factory starring Danny Dyer and many more.

Still without it, would the world have what the US call EDM and what others call the Rave culture?

This is very likely false; a myth perpetuated from the war on drugs combined with people taking unknown, untested substances in recreational settings.

If they experienced serotonin syndrome it was quite easy to just point at the reported seratonergic substance that had been ingested (and which also may not have been present at all, depending on the source).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931730/

The worst cases are likely from interplay with other medications or simply overheating.

However, the same is repeated in literature about plain methamphetamine, not just methylene-dioxy-methamphetamine, so I would not entirely trust the current state of science on this.

It’s repeated for lots of medications where it could never happen. SS is widely misunderstood even in the medical community.

I trust specific doctors who specialize in psychedelic medicine and psychiatry who have deep understanding of the metabolic pathways and pharmacokinetics of these substances.

https://www.pharmacytimes.com/view/serotonin-syndrome-myths-...

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8820588/

Just curious if you have been around people who take a lot of MDMA (I don't know what the "abuse" threshold is) or you have yourself.

It does "something" to your cognitive abilities that is not beneficial. I don't know how permanent it is. Probably recoverable in most cases?

Maybe not using 3 time a year (or whatever) but multiple times per week for months on end yes, it makes a person get "funny in the head". I've seen it with more then one person.

I'm not anti drug nor denying therapeutic use (makes sense) but I'm fully convinced from observation MDMA is not risk free or harmless, especially when used to excess. Yes, anecdotal. But just a word of advice for whatever it's worth.

I don't think even the most hardcore pro-drug advocates would claim that using MDMA multiple times per week is ever safe, but is there any evidence that that kind of abuse is remotely common? On average taking ecstasy is safer than riding a horse [1], and if you really just love to get fucked up and don't care about burning a hole in your brain, why not just graduate to straight-up meth?

[1]: https://en.wikipedia.org/wiki/David_Nutt#%22Equasy%22

I don't know how common that kind of usage is. This was a group of people I hung with back in the 90's.

The dangers of riding a horse are immediately apparent and it's easy to link cause and effect. Additionally the damage from a bad horse ride (unless you hit your head) are more likely to be physical trauma, a broken leg etc.

The (possible) negative effects of a drug on cognition are more subtle and harder to attribute.

Again, I'm not anti drug at all (especially legally speaking).

It's just, what I saw and I feel I should relate it as a bit of a cautionary tale. I am convinced overuse of MDMA has a negative effects on the kind of cognition that allows a person to plan, link cause and effect, think abstractly and that kind of thing. It's not a scientific study, just what I believe from observation.

Here is how I think about it: your cognitive processes are accustomed to certain biochemical biases. You’ve grown and developed your brain in response to stimuli under a certain set of conditions.

One set might be jacked adrenals due to your propensity for epic soundtracks and caffeine or chocolate consumption.

Another set might be alcohol and social feedback.

If you spend a lot of time in these states, your unbiased function diminishes because you are optimizing for a different chemical bias.

If you are not so far gone, or are exceptionally motivated or introspective, you can integrate those experiences, and it might expand your awareness. If you can’t, or don’t, it might increase your function while using but reduce your sober function. This effect will increase as you spend more and more time ‘high’: you are transitioning function within your own constrained cognitive capacity to a different bias.

So you're kinda on the right track. What happens is that we have a specific range of regulation that our neurotransmitters and receptors etc fall into based on our genetics which could be a bit modified through epigenetic means.

That range of regulation is what we drift towards when we start adapting to an exogenous compound (some drug) that is consistently present through repeated dosing.

Considering that information, we do adapt to become "normal functioning" (according to the previously mentioned genetics) and it becomes more difficult again when we suddenly remove the drug (again forcing us out of that range that our genetic regulatory mechanisms would like us in)

During periods that we are using the exogenous compound we can form new habits driven by changes made by the drug which can stick around after removal, as removal of the drug won't suddenly undo many of the synaptic changes that occurred. I think this is what we can call the integration of experiences and I think that long term potentiation is a big factor in those changes (which is a pretty neat topic on its own, I'd recommend reading about LTP if you want to understand some of the mechanisms of learning)

> multiple times per week for months on end yes

that is not use but abuse, and I'd expect bad consequences.

That sums it up very succinctly, thank you.

Modern society does a pretty good job of that already. How many prescriptions for antidepressants do we issue in the western world? tl;dr, I consider them lower risk than horse riding, or working in a startup.

Most 78 year old men who aren't dead don't really have the mental faculties to clearly lecture a university at 78.

A soda a day rots far more brains than an occasional trip.

Or even a lot of trips, judging by all the famous old psychonauts who were still lecturing in their 70s, 80s, 90s, and even 100s.

And the less-famous old psychonauts now training your EMS/fire staff, running software departments, working as school principals, etc. Don't forget about the rank and file!

100%. Here’s a book of interviews of elderly psychonauts.

https://books.google.nl/books?id=wL5G8s3xpxwC&lpg=PR11&ots=w...

Love how pretentious the term "psychonaut" sounds.

Edit: I'm not a smoker, I'm a toxicnaut.

When the DARE officer said stuff like this to us as 7th graders, we laughed.

It's maybe less funny today but ridicule remains the appropriate response.

The DARE officer said drugs would fry your brain, and the kids taking and selling drugs said it was a lie to stop people from having an easy harmless good time. Considering the drugs that kids were taking at my high school, I wouldn't say either side covered themselves in glory.

> I wouldn't say either side covered themselves in glory.

heh. that's mostly fair, though DARE waged a propaganda campaign entirely unmatched by teenage druggies, who are mostly just people trying to get by.

Isn’t his partner like 92 and still spreading the good word? Folks want to link his chem experimentation to negative health outcomes to justify their own “drugs are bad mkay” beliefs. In the end, he literally cataloged all the chems and lived to 88… if I were going to choose a single case to illustrate this hypothesis-> this psychonaut would not be it. In fact, I probably wouldn’t even want him in my sample if I were going to try and prove the hypothesis.

> Folks want to link his chem experimentation to negative health outcomes to justify their own “drugs are bad mkay”

Drugs, prescription or not, can be very bad when used in excess or ignorance. These people know what they're putting in their bodies, and have the knowledge and means to test or even make them, but the majority of drug users don't.

Well, we have made most interesting exploratory drug use illegal for most people, so that historically most people who use drugs are those with nothing left to lose.

The best way to advance may be to let more smart people try drugs without artificial consequences.

Like, “a license to trip” kind of thing? Love it.

Terrance McKenna died at 53.

Dose is probably important in all this but it’s hard to say with such a small, probably biased, sample size.

He died of glioblastoma and there's absolutely zero evidence that it was related to drug use.

https://en.m.wikipedia.org/wiki/Glioblastoma

I know that. There’s also zero evidence that any of the drugs that these people have taken have extended their lives. They’re absolutely zero studies that show that these compounds are either safe or dangerous. Anyone saying that they’re either has a bias.

And there is no evidence that McKenna’s drug use did not cause his brain cancer. Absence of evidence is not evidence of absence. The best we can say is that we do not know.

"They’re absolutely zero studies that show that these compounds are either safe or dangerous."

There are lots of studies on the safety of psychedelics.

> They’re absolutely zero studies that show that these compounds are either safe or dangerous. Anyone saying that they’re either has a bias.

Your ignorance does not indicate lack of research in the real world.

<https://en.wikipedia.org/wiki/David_Nutt>

In 2007 Nutt published a controversial study on the harms of drug use in The Lancet.[17] Eventually, this led to his dismissal from his position in the Advisory Council on the Misuse of Drugs (ACMD); see government positions below. Subsequently, Nutt and a number of his colleagues who had subsequently resigned from the ACMD founded the Independent Scientific Committee on Drugs, which was later re-named Drug Science.[18]

(read: the uk government didn't like what he had to say, that drugs weren't totally appalling meritless things, so they sacked him)

from that wiki page

<https://en.wikipedia.org/wiki/File:HarmCausedByDrugsTable.sv...>

<https://en.wikipedia.org/wiki/File:Development_of_a_rational...>

But the next time drugs comes up you'll doubtless post the same thing.

> there are absolutely zero studies that show that these compounds are either safe or dangerous.

there are many studies about these medicines - curious where this statement that there are none is coming from?

here's a tip of the iceberg, a good place to start --

https://www.nature.com/articles/s41591-021-01336-3

https://www.tandfonline.com/doi/abs/10.3109/00952990.2016.11...

https://www.hopkinsmedicine.org/news/newsroom/news-releases/...

https://www.hopkinsmedicine.org/news/media/releases/hallucin...

https://www.hopkinsmedicine.org/news/media/releases/magic_mu...

For what it's worth I agree with you both: you, green new shoot on HN, and also the other commenters disagreeing with you. Because I think there are studies that shows psychedelics are safe you but they're safe within a certain context of analysis done in the study. I think you're right we don't know if there's any cause between taking psychedelics and cancers. Glioblastoma is a connective tissue cancer of the brain I think and I think it's not inconceivable to consider that psychedelics in that they induce a proliferation of new neurons and connections and so they could somehow effect an overgrowth of connective tissue (btw I know connective tissue is different to neuronal connections...heh :) but still it may be connected ;) in various ways). Whether it's conceivable or not doesn't really matter cuz there's plenty of things that occur in the body which aren't conceivable at some point in time. So I think the best we can say is they're probably safe but we don't really know...and that's just the way it is. Even so the risk albeit a personal thing is low for causing something as disastrous as that aggressive tumor and the fact that we don't know doesn't make it in any different to the infinite number of other possible causes of glioblastoma or whatever severe acute illness that we don't know are causes either. I think your point is valid and correct and people have maybe taking it in a way that may have abandoned the nuance with which it was delivered.

Also I was interested by your other comment suggesting I think that B6 could increase indogenous production of HT-something in the body... Did I get that right? Could you maybe point me to the direction of more of that type of information?

I'm fairly certain that sitting at a computer working 8-10 hour days of physical inactivity is far worse on the human body than moderate use of psychedelics.

> all three of which are likely consequences of taking psychedelics frequently

You can't know that. Those are pretty common diseases of advanced age. It might've been the drugs, it might not.

"Well I mean, at the end of Shulgin's life he had heart valve damage requiring surgery (psychs cause 5-HT2B agonism which can cause heart valvulopathy), advanced dementia, and liver cancer, all three of which are likely consequences of taking psychedelics frequently."

His wife took as many psychedelics as he did, right along with him, and she's fine.

People have played Russian roulette and survived. Clearly then, Russian roulette is harmless.

I'm not claiming that doing what Shulgin did was harmless. I was replying to an anecdote of one with a comparable anecdote of one.

With this kind of super-heavy use of novel psychoactive substances, there really can never be anything but anecdotes. We'll never see double-blind studies of large groups of people taking all the substances that the Shulgins took over their lifetimes, so anecdotes are all we have.

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